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Thyroid hormone action plays an important role in the regulation of many physiologic processes, among them glucose and lipid metabolism. Interestingly, the clinical presentation of thyroid dysfunction is extremely variable, with relatively poor correlation between circulating hormone levels and clinical features. This finding suggests that the local, intracellular concentration of the active hormone liothyronine (T3), regulated by peripheral conversion of the pro-hormone levothyroxine (T4), is an important determinant in the maintenance of the thyroidal homeostasis.
The aim of the present study is the evaluation of the role of peripheral thyroid hormone conversion in the regulation of glucose and lipid metabolism by assessing the differential response to T4 or T3 treatment in subjects devoid of endogenous thyroid hormone production. T3 administration bypasses peripheral metabolism and therefore will allow us to assess the role of peripheral thyroid hormone conversion in the regulation of hormone action at the end-organ level.
Fifty thyroidectomized subjects will be initially randomized to either of the thyroid hormone replacements liothyronine (T3) or levothyroxine (T4), aimed to maintain serum TSH levels ?0.5?1.5 mU/L, indicating full replacement. After a 30-day period of steady-state replacement the study subjects will be admitted to the NIH Clinical Center and, after a three-day period of stabilization and an overnight fast, will undergo the following tests: escalating dose TRH stimulation test, indirect calorimetry, graded exercise tolerance test, DEXA scan, and echocardiogram.
Patients will also undergo skeletal muscle biopsy and subcutaneous adipose tissue biopsy and microdialysis, as well as a two-step euglycemic hyperinsulinemic clamp with measurement of splanchnic gluconeogenesis. Fasting venous blood samples will be collected for the determination of the parameters of lipid, glucose and energy metabolism. After discharge, the patients will switch to the other form of thyroid hormone replacement therapy. The therapy will be adjusted in order to achieve the same therapeutic goal for TSH concentrations (?0.5?1.5 mU/L), analogous to that achieved during the first phase of the study (TSH ?0.5 mU/L difference between T3 and T4 phases). After reaching a 30-day period of steady-state replacement, study subjects will be re-admitted to the Clinical Center and the previously described procedures will be repeated.
